This application is the competitive renewal application of NIH MH-42088, seeking five years of support, which would represent years 15-19 of this project on the Psychobiology of Corticotropin-Releasing Factor (CRF). In the past years, this grant has provided much evidence for a preeminent role for CRF-containing neurons in mediating the response, characterized in considerable detail the neurotransrnitter role of CRF in the mammalian CNS, and perhaps most importantly, contributed to the burgeoning dah base which supports the hypothesis that CRF is hypersecreted in patients with major depression. Indeed, contributions from this and other laboratories using a variety of multidisciplinary approaches have provided unequivocal evidence for hyperactivity of CRF-containing in neurons patients with major depression, particularly those patients with severe depression. The current proposal seeks to extend this work in directions largely based upon findings obtained during the current funding period (aims I & 2 in a new direction as well (genetics aims 3 & 4). Specifically, the investigators wish to continue the postmortem brain tissue studies to further characterize that alterations in CRF-containing neurons and CRF receptor-containing neurons by scrutinizing CRF and CRF receptor mRNA expression, as well as focusing on the CRF2 receptor and urocortin The development of small molecule, non-peptide CRF1 receptor antagonists has occurred to some extent due to the investigators progress in this field. With their increasing availability, the behavioral, endocrine, and neurochemical responses chronic administration of these CRF1 receptor antagonists will be characterized. Moreover, the responses to discontinuation of these compounds will be assessed. In a novel animal model of depression based upon sensitivity stress in the forced-swim test that is highly sensitive to all classes of antidepressants, the investigators will determine whether CRF1 receptor antagonists exhibit an antidepressant profile. Moreover, are alterations in CNS CRF neuronal systems and receptors present in this animal model? Because evidence suggests that altered CRF function appears to be responsible, at least in part, for the anxiety and/or depression phenotype in some animal models, the investigators will map the quantitative trait loci (QTL) that control the expression of the CRF system. These studies will provide novel information on the role of CRF nepronal systems in the pathophysiology of depression, in animal models of systemic CRF1 receptor antagonist administration.